EU Directives EU Legislation • 2001/20/EC • 2005/28/EC • EudraLex Vol 10 Pharmacovigilance Legislation, SOPs and Reporting Louise Boldy, Governance & Safety Manager David Martin, Pharmacovigilance Monitor UK Law • SOP 11 – Identifying, recording and Statutory Instruments reporting AEs for CTIMPS 2004/1013 (primary legislation) 2006/1938 (amendments) • SOP 15 – Preparing and submitting 2006/2984; 2008/0941; progress & safety reports 2008/3097 Roles and Responsibilities Sponsor Responsibilities Accountable for overall conduct of the trial Regulatory Agency MHRA Responsible for ongoing safety evaluation of the IMP. – Protect the safety of current and future patients involved in a study. – Develop & establish overall safety profile of IMP. Is expected to undertake their own assessment of Investigator Sponsor SAEs and decide if they are SARs or SUSARs
Sponsor Requirements Investigator Responsibilities • Report UK SUSARs to MHRA and • Must record all AEs during a study main REC within defined timelines – records can be inspected by the Sponsor –Fatal/life-threatening within 7 days • decide if an event is serious –Non-fatal/life-threatening within 15 days • decide if an event is a reaction • SUSARs now reported electronically • decide if a reaction caused by IMP • Must immediately notify the Sponsor of • Annual Safety Reporting SAE/Rs (usually within 24 hrs). Investigator Responsibilities • Trial design • Patient recruitment and safety SOP 11 • IMP accountability • Accuracy of results • Analysis and interpretation IDENTIFYING, RECORDING • End of Trial Declaration (MHRA, Ethics) AND REPORTING ADVERSE EVENTS FOR CTIMPS • End of Trial Report What is an Adverse Event? What information is needed to report an event? “ any untoward medical occurrence in a Sufficient information to identify: patient or clinical trial subject administered a medicinal product and which does not – The clinical trial necessarily have a causal relationship with – The trial subject this treatment” – The event – The IMP – The reporter Directive 2001/20 EC
Is it serious? If the Adverse Event is Serious… • results in death “ The investigator shall report all serious adverse • is life-threatening events immediately to the sponsor except for • required inpatient hospitalization or those that the protocol or Investigator’s Brochure prolongation of existing hospitalisation identifies as not requiring immediate reporting. The immediate report shall be followed by • results in persistent or significant disability detailed written reports”. or incapacity • is a congenital anomaly or birth defect Directive 2001/20 EC • is otherwise considered serious - Article 16 (ICH Guidelines for GCP) Is it a Reaction? Recording and Reporting Marketed medicinal products: • All Adverse Events must be recorded – A response to a drug which is noxious and – Case Report Form (CRF) unintended and which occurs at doses – Adverse Event Log normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function. • Serious Adverse Events must be reported to the sponsor (ICH Guidelines for GCP) Is it expected? What happens to your SAE? • Clarify what section(s) of the IB/SPC are • Check for completeness and signature being used to assess expectedness. • Assess for expedited reporting • Enter into Pv database • Any person making expectedness • Assign WHO-ICD code assessments must understand the • Confirm receipt and code to investigator, check regulatory definition that code is appropriate – An adverse reaction the nature or severity of • Arrange for independent clinical review which is not consistent with the applicable – complete subsequent actions product information. • Follow up SAE to resolution if required • If multiple people are performing these • Expedited reporting to MHRA if required assessments there must be consistency.
Expedited Reporting Requirements • Adverse Reaction • Serious If the IMP is suspected of being the cause of • Unexpected a serious adverse reaction it must be • Suspected reported to the MHRA within… – Seven days if fatal or life-threatening = SUSAR – Fifteen days for other suspected reactions Other Reporting Requirements Question 1 • It is the sponsor’s responsibility to keep all investigators undertaking clinical trials for which they are also acting as sponsor informed of SUSARs, If a subject is treated in A&E where such trials also involve the same IMP. but not admitted to hospital, • Reports sent to the Investigator regarding SUSARs from other trials of the same medicinal product must is this an SAE? be reviewed by the Investigator and acted upon if appropriate. Copies of such SUSAR reports must be kept in the ISF and the TMF. Answer 1 Question 2 • Probably not, but… • Is it covered in the protocol? • What did the subject attend A&E for? If a subject is admitted to • Could it be otherwise considered serious? hospital for a pre-planned • If the decision is not to report the event as serious, it must be entered in to the AE log operation, is this a SAE?
Answer 2 Question 3 A well known side-effect of product X is • Probably not but… hypotension. A trial subject is hospitalised • This should be covered in the protocol. due to hypotension after receiving the • If elective surgery is excluded in the product. protocol an event may still be reportable if: – Complications arise which cause prolongation Does this still need to be reported to the of hospital stay Sponsor as a SAE? – The IMP is possibly linked to any drug interactions during the hospital stay Answer 3 • Yes – unless excluded by the protocol SOP 15 Even if excluded – did the reaction occur with greater than PREPARING AND SUBMITTING expected severity, or rapidity of onset? PROGRESS AND SAFETY REPORTS Reporting Annual Safety Reports (CTIMPs) • Annual Safety Reports — becoming… • Annually from date of CTA approval – Development Safety Update Reports • Prepared by TASC on behalf of the Chief Investigator • Annual Progress Reports • Prepare ASR • Pregnancy Reporting • Line listing of SARs • Expedited Reporting • Send to CI for checking and IMP safety • Urgent Safety Measures assessment. – Submit to MHRA • Other Reporting Requirements – Submit to REC
Development Safety Update Reports Annual Progress Reports DSURs • Annually from date of REC approval • Annually, on the International Birth Date of • NRES annual progress report form the IMP (CTIMPs or non CTIMPs form) • First annual progress report should state • Includes all trials which use same IMP the commencement date for the study or an explanation for the delay . Pregnancy Reporting Expedited Reporting • Not considered an AE or SAE • The following safety issues should also be reported by the Investigator to the Sponsor in an expedited fashion: • Unless a congenital abnormality or birth defect – An increase in the rate of occurrence or a qualitative change of • Should be notified on pregnancy reporting forms (TASC expected SAR, which is judged to be clinically important. website) – Post-study SUSARs that occur after the trial participant has completed a clinical trial and are notified to the Investigator. – New events related to the trial or the development of the • Pregnancies of a trial participant or the female partner of investigational medicinal products and are likely to affect the a trial participant should be followed up to outcome safety of the participants. – Recommendations of the Data Monitoring Committee where • For female partners of male trial participants, consent is relevant for the safety of trial participants. required • The Sponsor is responsible for informing the MHRA and the REC of these safety issues. Urgent Safety Measures Where to find the forms • CI or PI at participating site may take appropriate safety measures to protect the • TASC Website participants of a CTIMP against any immediate http://www.tasc-research.org.uk/_page.php?id=269 hazard to their health or safety • Please use live forms as they may change • Urgent safety measures can be implemented • Adverse Event Log immediately • SAE form, and guidance • Investigator should contact Clinical Trial Unit at • Pregnancy Notification Form MHRA and discuss with a medical assessor. • Pregnancy Follow Up Form • Sponsor and REC should also be contacted at this time • Investigator must notify MHRA, REC and sponsor in writing within 3 days
Contact details Pharmacovigilance Department TASC R&D Office Ninewells Hospital and Medical School Residency Block, Level 3 Dundee DD1 9SY Email: pharmacovigilance.tayside@nhs.net Fax: 01382-740122 Telephone Direct: 01382 740296 (40296 internal) Admin: 01382 632236 (32236 internal)
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